title: MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis.
abstract: Because miR-146a is linked to osteoarthritis (OA) and cartilage degeneration is associated with pain, we have characterized the functional role of miR-146a in the regulation of human articular cartilage homeostasis and pain-related factors. Expression of miRNA 146a was analyzed in human articular cartilage and synovium, as well as in dorsal root ganglia (DRG) and spinal cord from a rat model for OA-related pain assessment. The functional effects of miR-146a on human chondrocytic, synovial, and microglia cells were studied in cells transfected with miR-146a. Using real-time PCR, we assessed the expression of chondrocyte metabolism-related genes in chondrocytes, genes for inflammatory factors in synovial cells, as well as pain-related proteins and ion channels in microglial cells. Previous studies showed that miR-146a is significantly upregulated in human peripheral knee OA joint tissues. Transfection of synthetic miR-146a significantly suppresses extracellular matrix-associated proteins (e.g., Aggrecan, MMP-13, ADAMTS-5, collagen II) in human knee joint chondrocytes and regulates inflammatory cytokines in synovial cells from human knee joints. In contrast, miR-146a is expressed at reduced levels in DRGs and dorsal horn of the spinal cords isolated from rats experiencing OA-induced pain. Exogenous supplementation of synthetic miR-146a significantly modulates inflammatory cytokines and pain-related molecules (e.g., TNFα, COX-2, iNOS, IL-6, IL8, RANTS and ion channel, TRPV1) in human glial cells. Our findings suggest that miR-146a controls knee joint homeostasis and OA-associated algesia by balancing inflammatory responses in cartilage and synovium with pain-related factors in glial cells. Hence, miR-146a may be useful for the treatment of both cartilage regeneration and pain symptoms caused by OA.
authors.affiliation: Department of Biochemistry, Rush University Medical Center, 1735 W. Harrison, Chicago, IL 60612, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Gary
authors.initials: G
authors.lastname: Gibson
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Kim
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kroin
authors.forename: Shunbin
authors.initials: S
authors.lastname: Xu
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
mesh_terms: D000818:Animals; D002358:Cartilage, Articular; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009434:Neural Pathways / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D010003:Osteoarthritis / Q000235:genetics*; D020370:Osteoarthritis, Knee / Q000235:genetics; D010146:Pain / Q000235:genetics; D051381:Rats; D013583:Synovial Membrane / Q000378:metabolism; D014162:Transfection
chemical_list: C542542:MIRN146 microRNA, human; C554180:MIRN146 microRNA, rat; D035683:MicroRNAs